Weinstein & Ciszek 2002.pdf

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B.S. Weinstein, D. Ciszek / Experimental Gerontology 37 (2002) 615±627

have programmed senescent cells to locally dismantle
the ECM, paving the way for their eventual replacement.
3.2. Lab mice and cloned sheep: life on strange
If individuals disperse from a high risk environment
to a low risk environment (e.g. a remote island) the
resultant increase in longevity will enhance the
potency of selection on late-life effects, eventually
slowing the rate of senescence (Williams, 1957;
Austad, 1993; Reznick, 1997). We expect that, in
such circumstances, selection increases telomere
lengths. This adjustment would come at some cost,
such as increased risk of tumors and/or an increased
burden from larger proto-tumors.
In the early part of this century, a small number of
Mus musculus dispersed into a novel environment: the
laboratory. In breeding colonies there is no predation,
no resource limitation and the spread of pathogens and
contaminants is controlled. Perhaps most signi®cantly, breeders are retired at 8 months (National
Research Council, 1981) so the mice that contribute
most to future generations are those that begin reproduction early, and sustain a high rate of reproduction
until the cut-off age. Such conditions are dramatically
different from those in the environment mice originally evolved to exploit, likely favoring a different
pattern of senescence.
The telomere systems of laboratory mice are hard to
reconcile with the notion of Hay¯ick limits as tumor
suppressors, or as the cause of senescence. Compared
to humans, lab mice have `ultra-long' telomeres,
exceeding human telomeres by an order of magnitude
(Kipling and Cooke, 1990). Further, somatic tissues of
lab mice produce telomerase, and can `spontaneously
immortalize' in culture.
One of us (BSW) predicted to Greider that long
telomeres in laboratory mice would be atypical for
mice in general. Hemann and Greider (2000) tested
this prediction with a survey of telomere lengths in a
number of mouse strains with shorter histories of
captivity than typical lab strains. All strains tested
had dramatically shorter telomeres, approximately
one tenth the length of telomeres in common lab mice.
The unusual telomere system of lab mice may be an
unintended consequence of captive breeding. Retire-

ment of breeders after 8 months eliminates selection
on late-life effects. Tumor-forming mutations take
time to occur, tumors take time to become lethal,
and the likelihood of tumor initiation is presumably
a function of the number of cells in the body, so in
small bodied animals like mice, tumors may be rare
and in¯ict minimal cost in the ®rst eight months of
life, even absent a telomeric fail-safe. Further, selection for sustained high reproductive output (beginning
early and maintained for 8 months) should strongly
favor a reduction in senescent effects occurring in that
window. Selection acting to eliminate senescent
effects and increase early reproductive output may
tend to elongate telomeres. Because of the inextricable connection between tumor suppression and
somatic maintenance, telomere elongation should
dramatically increase the risk of eventual tumor
formation, but any effects manifesting after the breeding cut-off will be selectively irrelevant. By our
model, selection for early high rates of reproduction
in the absence of selection for longevity or tumor
suppression should produce long telomeres and a
strong propensity for eventual tumor incidence.
Despite diminished senescence, we expect these
mice to have reduced maximum longevity compared
to wild conspeci®cs. At all ages, lab mice (with elongated telomeres) should be more likely to die of
tumors than wild mice. These mice should also be
unusually resilient to somatic damage and show few
signs of aging other than tumor formation. Alexander
(1966) presents evidence consistent with this pattern:
The most striking fact is that even very old [lab]
mice (e.g. more than 2.5 years) when killed
while still ®t have remarkably few pathologies
and are almost indistinguishable from young
The hypothesis that an 8 month breeding cut-off
should select for non-senescent, tumor prone mice
seems paradoxical. One might expect the elimination
of selection on late life effects to accelerate senescence, not retard it. But in lab mice, selection for
high, sustained rates of breeding appears to be the
dominant factor. The tumor fail-safe has effectively
been turned off, condemning these animals to form
tumors, but leaving an early-life window of reproduction within which there is minimal senescent decline.
This would likely not occur in much larger mammals,